INSULATING AGAINST RESISTANCE
Recent insights into the risk factors predisposing people to type 2 diabetes are leading researchers to new prevention and treatment strategies.
If Thomas Buchanan, M.D., were to ever wonder whether his work at the Keck School of Medicine makes a difference, he would just have to visit the home of a woman participating in one of his diabetes studies.
In it, he would likely find no insulin syringes, no glucose monitors and no test strips—because despite the odds against it, the woman would not have developed diabetes.
Buchanan’s research points to ways to prevent diabetes in those at high risk of developing it. And he is just one of the dozens of investigators at the USC Diabetes Research Center who are fighting against a disease that causes or contributes to hundreds of thousands of deaths in the United States each year.
The team of scientists and physicians, working in a variety of labs at USC, recently shared their latest work with international scientists at the American Diabetes Association’s annual meeting in Philadelphia. And the spectators saw signs for optimism, because researchers are rapidly advancing on diabetes, seeking causes of the enigmatic disease as well as ways to prevent and treat it.
Saving cells
In the basement laboratory of Peter Butler, M.D., USC professor of medicine and chief of the division of endocrinology and diabetes, pancreatic beta cells—the cells that make insulin, which helps the body use glucose for energy—struggle between life and death.
Their outcome may someday point to a better life for diabetes sufferers.
Faced with the mysteries of how beta cells decay, Butler and his colleagues had to come up with a method to watch them over time. So Robert Ritzel, D.Sc., a postdoctoral fellow in Butler’s lab, invented a surveillance system—time lapse video microscopy—to observe what happens to beta cells in diabetes. The result: new insights into how diabetes works.
When beta cells produce insulin, Butler explains, they also pump out a protein called human islet amyloid polypeptide, or IAPP, thought to help regulate blood sugar. But in type 2 diabetes, this protein starts clumping into strings, eventually forming abnormal, insoluble deposits in the pancreas called amyloid.
Butler’s team found that when IAPP clusters into abnormal threads, beta cells often die—killing themselves in a process called apoptosis. And the cells most vulnerable are those reproducing and renewing themselves most actively.
Finally, when team members applied the abnormal protein to human islets—clusters of pancreatic cells that include beta cells—they saw damage: the islets swelled and loosened, jettisoning cells like passengers off a sinking ship.
Butler believes that in healthy people, beta cells channel IAPP without forming toxic, abnormal chains. Because of genetics, though, people vulnerable to type 2 diabetes may have less capacity to withstand IAPP.
That is okay in those who are lean and athletic, because their bodies make small amounts of IAPP. But with increasing weight and hours logged as a sedentary couch potato (risk factors for type 2), IAPP production soars.
Eventually, the rate of beta cell destruction outpaces the rate of beta cell replacement, leading to diabetes, he suggests.
The research may lead to new prevention or treatment strategies for diabetes—and even other disorders characterized by similar plaque deposits, such as Alzheimer’s disease.
Where’s the fat?
The years preceding a diagnosis of type 2 diabetes may seem benign. Yet while they show no symptoms, patients may be slowly growing resistant to insulin.
Richard N. Bergman, Ph.D., chair of the Department of Physiology and Biophysics at the Keck School, may have found a key risk factor predisposing people to insulin resistance.
Non-scientists might dub it the “spare tire” effect.
According to study results, fat around the abdomen is more likely than fat elsewhere to trigger the liver to make glucose and lead to abnormal glucose metabolism.
“This is the issue of apple-shaped versus pear-shaped people,” Bergman says. “A woman with a lot of adiposity in her rear end, for instance, is not at as much risk as a woman whose fat is located centrally.”
Why? Location. Fatty acids from the abdomen may be more likely to go into the blood and beeline to the liver, where glucose is made. (The liver can police the level of glucose by making it or removing it from blood). If the abdomen releases too many fatty acids, that might cause the liver to make too much glucose, Bergman explains.
After a while, elevated glucose can lead to insulin resistance.
“Normally, insulin should suppress the release of glucose, but when so much glucose is being released that insulin can’t properly suppress it, that’s tantamount to insulin resistance,” Bergman says. “And that seems to be what’s happening here.”
Now Bergman and his team will investigate just how fatty acids contribute to insulin resistance, and how they work to boost glucose production from the liver.
Cellular vacation
As scientists uncover diabetes’ causes, others—including Buchanan, Keck School professor of medicine, obstetrics and gynecology and physiology and biophysics—strive to prevent the disease.
Buchanan’s team identified more than 200 Latinas in Los Angeles who had gestational diabetes, a form of diabetes occurring during pregnancy. Although gestational diabetes usually disappears after childbirth, patients commonly continue to be resistant to their own insulin, and up to half of them develop type 2 diabetes within a few years.
So, knowing the women faced high risk for diabetes, Buchanan gave them daily troglitazone or a placebo. (At that time, physicians routinely prescribed troglitazone to treat type 2 diabetes, because it
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DIABETES CHEAT SHEET Diabetes occurs when the body does not make enough insulin, does not use insulin effectively, or both. Clumps of cells called islets in the pancreas make insulin. Insulin is a hormone that helps the body use glucose, the body’s main energy source. Most people with diabetes have one of two kinds: type 1 or type 2. Type 1 diabetes is an autoimmune disease, which means that the immune system attacks the body’s own beta cells—part of the islets—which make insulin. Type 1 diabetes accounts for approximately 10 percent of all cases of diabetes. Type 2 diabetes is far more common, accounting for approximately 90 percent of all cases. In type 2, beta cells make insulin, but the body is resistant to the hormone. Insulin is supposed to help the body’s cells take up and use glucose, but for some reason, cells do not respond as they should. Beta cells are overworked and, in some people, they wear out and stop making the right amount of insulin. In both cases, too much sugar stays in the blood and can cause damage to the eyes, kidneys, nerves and blood vessels.
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helps cells better use insulin to absorb glucose. When the U.S. Food and Drug Administration recalled that drug in 2000, USC researchers switched to another similar FDA-approved drug.)
When muscle and fat cells grow resistant to insulin, beta cells compensate by working hard to produce more insulin. Over time, this makes them wear out in some people and produce less or no insulin, causing type 2 diabetes. Buchanan and colleagues believed if they could lessen the workload by giving the drug, they might keep beta cells from failing, thus preventing diabetes.
Over 30 months, women taking troglitazone were diagnosed with diabetes less than half as often as those not taking the drug.
The drug seemed to help very insulin-resistant women the most. When these women started the study, their beta cells were laboring hard, secreting lots of insulin. But when women took troglitazone, the cells had to do far less work. Women whose beta cells had a smaller decline in their workload were not as protected by the drug, and some women developed diabetes despite taking troglitazone.
“This fits with the idea that beta cells can wear out through chronic insulin resistance,” Buchanan says. “It was the women whose beta cells were working hardest at the start of the study who had the greatest benefit from the drug. That was because their beta cells got the greatest amount of ‘rest’ during treatment.”
Importantly, researchers found that the drug actually prevented the disease, rather than merely masking it during the time the women took the drug. When they stopped taking the drug for eight months, they remained free of diabetes.
Now the team is striving for more, trying to understand why some peoples’ beta cells wear out, while others’ do not. They have tested siblings of women with gestational diabetes to see if they, too, have a beta cell defect. It appears to run in families. Studies are underway to find the genes underlying the risk for this beta cell failure. Knowing the genes will allow Buchanan and his colleagues to design better ways to predict and prevent diabetes.
Fit or fat
Key to prevention, too, is encouraging good eating and exercise habits. At Childrens Hospital Los Angeles (CHLA), Francine Kaufman, M.D., Keck School professor of pediatrics, and her diabetescolleagues work to keep kids healthy—a challenge when fast food and television beckon.
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WHERE WELLNESS DWELLS It has the air of a place of wellness and care, calm and worry-free. A day spa, perhaps? Close, but not quite. The USC Westside Center for Diabetes offers neither massages nor mud baths, but its focus on wellness might just tempt clients to ask if they are offered. “We see it as a welcoming place, where we can form partnerships with patients,” says Anne Peters, M.D., USC professor of medicine and center director. "Type 2 diabetes is a disease of lifestyle, really,” Peters says. “Adjusting lifestyle can help prevent complications and make it manageable. The idea is to promote behavior modification in one unified, affordable program." Physicians, nurses, dietitians and other team members offer a spectrum of diagnostic, treatment and preventive services. Treatment from doctors and nurses links with customized counseling in exercise and diet. Patients, from adults to children, have access to treatment drawing from the latest clinical research and technology. All necessary tests are done in one location. Staff members initiate and follow up on patients' insulin pump therapy, as well as perform immediate blood tests and measure HbA1c (glycosylated hemoglobin) levels to assess patients' blood glucose control. Computerized downloading for patients' glucose meters allows physicians to analyze data while patients are still in the clinic—without an extra visit. The center also stresses prevention, screening people at high risk for diabetes and using strategies to slow diabetes onset and progression. ?
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The percentage of young people considered overweight has nearly doubled in the last 20 years, experts say. Obesity increases risk of type 2 diabetes.
The team created a family-centered activity and nutrition program called Kids-N-Fitness, successfully getting children to exercise, eat better and recognize habits that lead to gaining weight.
Eight 90-minute sessions focus on eating and exercise behavior. Activities include building food pyramids, supermarket shopping, low-calorie eating for a day and identifying habits that lead to weight
gain. Children also do aerobics, volleyball, soccer and calisthenics, and parents get involved too.
Participants are found to gain significantly less weight per month, exercise more and increase their fruit and vegetable consumption.
“The children come to the sessions eager to participate and leave more fit and knowledgeable, without having gained weight,” says Marsha D. MacKenzie, R.D., C.D.E., head of the Endocrine and Obesity Nutrition Program at CHLA.
Besides prevention, the researchers also look for ways to improve treatment.
Knowing that diabetes patients face possible cardiovascular problems, researchers at the Keck School and CHLA looked at the heart health of young adults with type 1 diabetes.
They found that by their teen years, patients with type 1 diabetes already have significantly more risk of atherosclerosis, or plaque buildup in their arteries, than their peers without diabetes. Researchers found that those with greater plaque buildup had higher levels of certain lipids in the blood, such as low-density lipoprotein, or LDL, the so-called “bad” cholesterol.
“The increased lipid levels in adolescents and young adults with diabetes, and the possible association with atherosclerosis, suggests that abnormal lipid levels may warrant intervention,” says Jody Krantz, M.D., a fellow in the division of endocrinology at CHLA.
Whether they cover prevention or treatment, adults or children, the USC researchers say that diabetes warrants the national attention it has been receiving—and they hope it continues.
“People are excited about the research,” says Buchanan. “But there’s still a lot more to do.” ?
For information about the USC Diabetes Research Center, or to learn more about The Doctors of USC, call 1-800-USC-CARE (1-800-872-2273.)
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